11

Anesthetic Agents and Therapeutic Gases

This chapter will be most useful after having a basic understanding of the material in Chapter 19, General Anesthetics and Therapeutic Gases and Chapter 20, Local Anesthetics in Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th Edition. In addition to the material presented here, the chapters in the 12th Edition include:

• Details of the general principles of surgical anesthesia

• A detailed discussion of the mechanisms of anesthesia

• The chemical structures of parenteral, inhalational, and local anesthetics

• A detailed discussion of therapeutic gases

• Figure 20-3 which is a depiction of the local anesthetic receptor site

• Table 20-1 Susceptibility to Block Types of Nerve Fibers

• A detailed discussion of the mechanisms of action of local anesthetics

• A detailed discussion of the various ways that local anesthetics are administered

LEARNING OBJECTIVES

   Learn the mechanisms of action of parenteral, inhalational, and local anesthetics.

   Understand the ways that anesthetics (parenteral, inhalational, and local) are used to facilitate surgical and other painful medical procedures.

   Know the major pharmacological properties and toxicities of anesthetic drugs.

MECHANISMS OF ACTION OF ANESTHETIC AGENTS

  CASE 11-1  

A 32-year-old woman is about to be anesthetized for her first time for a surgical procedure.

a. What is anesthesia? What are important general issues concerning anesthesia to be aware of?

General anesthetics depress the CNS to a sufficient degree to permit the performance of surgery and other noxious or unpleasant procedures. The components of anesthesia are shown in the Side Bar COMPONENTS OF THE ANESTHETIC STATE. The general principles of anesthesia are listed in the Side Bar GENERAL PRINCIPLES OF SURGICAL ANESTHESIA.

Inevitably, anesthetics also suppress normal homeostatic reflexes. The most prominent physiological effect of anesthesia induction, associated with the majority of both intravenous and inhalational agents, is a decrease in systemic arterial blood pressure. Airway maintenance is essential following induction of anesthesia, as nearly all general anesthetics reduce or eliminate both ventilatory drive and the reflexes that maintain airway patency. Therefore, ventilation generally must be assisted or controlled for at least some period during surgery.

Patients commonly develop hypothermia (body temperature <36°C) during surgery. Prevention of hypothermia has emerged as a major goal of anesthetic care.

Nausea and vomiting in the postoperative period continue to be significant problems following general anesthesia and are caused by an action of anesthetics on the chemoreceptor trigger zone and the brainstem vomiting center.

Pain control can be complicated in the immediate postoperative period. The respiratory suppression associated with opioids can be problematic among postoperative patients who still have a substantial residual anesthetic effect. Regional anesthetic techniques are an important part of a perioperative multimodal approach that employs local anesthetic wound infiltration, epidural, spinal, and plexus blocks. Nonsteroidal anti-inflammatory drugs, opioids, α₂-adrenergic receptor agonists, and NMDA-receptor antagonists are commonly used as analgesics.

b. What are the different types of anesthesia?

The type of anesthesia generally depends on the type of surgery being performed and whether the surgical procedure is being performed on an outpatient basis. There are parenteral, inhalational, and local anesthetics. These are discussed in the following cases.

c. What are the mechanisms of general anesthesia?

The mechanisms by which general anesthetics produce their effects have remained one of the great mysteries of pharmacology. The current thinking on the cellular and molecular mechanisms of anesthesia is shown in the Side Bar MECHANISMS OF ANESTHESIA.

In principle, general anesthetics could interrupt nervous system function at a myriad of anatomic sites, including peripheral sensory neurons, the spinal cord, the brainstem, and the cerebral cortex. Delineation of the precise anatomic sites of action is difficult because many anesthetics diffusely inhibit electrical activity in the central nervous system (CNS).

  CASE 11-2  

The patient in Case 11-1 will be given a parenteral anesthetic as an inducing agent.

a. Why give an inducing agent?

Inhalational anesthetics are often irritating and onset of anesthesia can be variable. Consequently, anesthesia is usually begun with a parenteral agent that has a rapid and predictable onset. The commonly used parenteral anesthetics and their pharmacological properties are shown in Table 11-1.

TABLE 11-1 Pharmacological Properties of Parenteral Anesthetics

b. What are factors that control onset and termination of effect of a parenteral anesthetic?

Hydrophobicity is the key factor governing the pharmacokinetics of parenteral anesthetics. After a single intravenous bolus, these drugs preferentially partition into the highly perfused and lipophilic tissues of the brain and spinal cord where they produce anesthesia within a single circulation time. Subsequently blood levels fall rapidly, resulting in drug redistribution out of the CNS back into the blood. The anesthetic then diffuses into less perfused tissues such as muscle and viscera, and at a slower rate into the poorly perfused but very hydrophobic adipose tissue. Termination of anesthesia after single boluses of parenteral anesthetics primarily reflects redistribution out of the CNS rather than metabolism (see Figure 11-1). After redistribution, anesthetic blood levels fall according to a complex interaction between the metabolic rate and the amount and lipophilicity of the drug stored in the peripheral compartments. Thus, parenteral anesthetic half-lives are “context-sensitive,” and the degree to which a t_1/2 is contextual varies greatly from drug to drug, as might be predicted based on their differing hydrophobicities and metabolic clearances (see Table 11-1 and Figure 11-2). For example, after a single bolus of thiopental, patients usually emerge from anesthesia within 10 minutes; however, a patient may require more than a day to awaken from a prolonged thiopental infusion.

FIGURE 11-1 Thiopental serum levels after a single intravenous induction dose. Thiopental serum levels after a bolus can be described by 2 time constants, t_1/2 α and t_1/2 β. The initial fall is rapid (t_1/2α<10 minutes) and is due to redistribution of drug from the plasma and the highly perfused brain and spinal cord into less well-perfused tissues such as muscle and fat. During this redistribution phase, serum thiopental concentration falls to levels at which patients awaken (AL, awakening level; see inset—the average thiopental serum concentration in 12 patients after a 6 mg/kg intravenous bolus of thiopental). Subsequent metabolism and elimination is much slower and is characterized by a half-life (t_1/2 β) of more than 10 hours. (Adapted with permission from Burch PG, and Stanski DR, The role of metabolism and protein binding in thiopental anesthesia. Anesthesiology, 1983;58:146-152. Copyright Lippincott Williams & Wilkins. http://lww.com.)

FIGURE 11-2 Context-sensitive half-time of general anesthetics. The duration of action of single intravenous doses of anesthetic/hypnotic drugs is similarly short for all and is determined by redistribution of the drugs away from their active sites (see Figure 11-1). However, after prolonged infusions, drug half-lives and durations of action are dependent on a complex interaction between the rate of redistribution of the drug, the amount of drug accumulated in fat, and the drug’s metabolic rate. This phenomenon has been termed the context-sensitive half-time; that is, the t_1/2 of a drug can be estimated only if one knows the context—the total dose and over what time period it has been given. Note that the half-times of some drugs such as etomidate, propofol, and ketamine increase only modestly with prolonged infusions; others (eg, diazepam and thiopental) increase dramatically. (Reproduced with permission from Reves JG, Glass PSA, Lubarsky DA, et al: Intravenous anesthetics, in Miller RD et al, (eds): Miller’s Anesthesia, 7th ed. Philadelphia: Churchill Livingstone, 2010, p 718. Copyright © Elsevier.)

c. What are the differences between the parenteral anesthetic agents?

Each of these drugs will produce anesthesia and the choice of which agent to use is usually based on its pharmacological properties. Table 11-1 lists the pharmacological properties of the parenteral anesthetic agents. Most individual variability in sensitivity to parenteral anesthetics can be accounted for by pharmacokinetic factors. For example, in patients with lower cardiac output, the relative perfusion of the brain and the fraction of anesthetic dose delivered to the brain are higher; thus, patients in septic shock or with cardiomyopathy usually require lower doses of anesthetic. The elderly also typically require a smaller anesthetic dose, primarily because of a smaller initial volume of distribution.

  CASE 11-3  

For the patient in Case 11-1, after induction of her anesthesia with a parenteral agent she is to be maintained with an inhalational anesthetic.

a. What are the choices of inhalational anesthetic agents to maintain anesthesia?

Table 11-2 lists the widely varying physical properties of the inhalational agents in clinical use. These properties are important because they govern the pharmacokinetics of the inhalational agents. Ideally, an inhalational agent would produce a rapid induction of anesthesia and a rapid recovery following discontinuation.

TABLE 11-2 Properties of Inhalational Anesthetic Agents

b. How is potency measured for inhalational anesthetics?

The potency of general anesthetic agents usually is measured by determining the concentration of general anesthetic that prevents movement in response to surgical stimulation. For inhalational anesthetics, anesthetic potency is measured in minimum alveolar concentration (MAC) units, with 1 MAC defined as the minimum alveolar concentration that prevents movement in response to surgical stimulation in 50% of subjects.

c. What are the pharmacokinetic principles of inhalational anesthetics?

In considering the pharmacokinetics of anesthetics, one important parameter is the speed of anesthetic induction. Anesthesia is produced when anesthetic partial pressure in the brain is equal to or greater than MAC. Because the brain is well perfused, anesthetic partial pressure in brain becomes equal to the partial pressure in alveolar gas (and in blood) over the course of several minutes. Therefore, anesthesia is achieved shortly after alveolar partial pressure reaches MAC. While the rate of rise of alveolar partial pressure will be slower for anesthetics that are highly soluble in blood and other tissues, this limitation on speed of induction can be overcome largely by delivering higher inspired partial pressures of the anesthetic.

Elimination of inhalational anesthetics is largely the reverse process of uptake. For agents with low blood and tissue solubility, recovery from anesthesia should mirror anesthetic induction, regardless of the duration of anesthetic administration. For inhalational agents with high blood and tissue solubility, recovery will be a function of the duration of anesthetic administration. This occurs because the accumulated amounts of anesthetic in the fat reservoir will prevent blood (and therefore alveolar) partial pressures from falling rapidly. Patients will be arousable when alveolar partial pressure reaches MAC_awake, a partial pressure somewhat lower than MAC (see Table 11-2).

d. What governs the speed of induction of an inhalational anesthetic?

It is essential to understand that inhalational anesthetics distribute between tissues (or between blood and gas) such that equilibrium is achieved when the partial pressure of anesthetic gas is equal in all tissues. When a person has breathed an inhalational anesthetic for a sufficiently long time that all tissues are equilibrated with the anesthetic, the partial pressure of the anesthetic in all tissues will be equal to the partial pressure of the anesthetic in inspired gas. Note, however, that while the partial pressure of the anesthetic may be equal in all tissues, the concentration of anesthetic in each tissue will be different. Indeed, anesthetic partition coefficients are defined as the ratio of anesthetic concentration in 2 tissues when the partial pressures of anesthetic are equal in the 2 tissues. Blood:gas, brain:blood, and fat:blood partition coefficients for the various inhalational agents are listed in Table 11-2. These partition coefficients show that inhalational anesthetics are more soluble in some tissues (eg, fat) than they are in others (eg, blood), and that there is significant range in the solubility of the various inhalational agents in such tissues.

For example, desflurane has a very low blood:gas partition coefficient (0.42) and also is not very soluble in fat or other peripheral tissues (see Table 11-2). For this reason, the alveolar (and blood) concentration rapidly rises to the level of inspired concentration (see Figure 11-3). Indeed, within 5 minutes of administration, the alveolar concentration reaches 80% of the inspired concentration. This provides for a very rapid induction of anesthesia and for rapid changes in depth of anesthesia following changes in the inspired concentration. Emergence from anesthesia also is very rapid with desflurane. The time to awakening following desflurane is shorter than with halothane or sevoflurane and usually does not exceed 5 to 10 minutes in the absence of other sedative agents.

FIGURE 11-3 Uptake of inhalational general anesthetics. The rise in end-tidal alveolar (F_A) anesthetic concentration toward the inspired (F_I) concentration is most rapid with the least soluble anesthetics, nitrous oxide and desflurane, and slowest with the most soluble anesthetic, halothane. All data are from human studies. (Reproduced with permission from Eger EI, II: Inhaled anesthetics: Uptake and distribution, in Miller RD et al, (eds): Miller’s Anesthesia, 7th ed. Philadelphia: Churchill Livingstone, 2010, p 540. Copyright © Elsevier.)

  CASE 11-4  

During anesthesia for the patient in Case 11-1, she will require endotracheal intubation.

a. What drugs are chosen for this?

Endotracheal intubation frequently requires the administration of a neuromuscular blocking drug to relax the muscles of the jaw. The pharmacology of these drugs is discussed in Chapter 6.

b. Why was the patient in Case 11-1 administered a benzodiazepine sedative prior to her surgery?

As adjuncts, benzodiazepines are used for anxiolysis, amnesia, and sedation prior to induction of anesthesia or for sedation during procedures not requiring general anesthesia. The benzodiazepine most frequently used in the perioperative period is midazolam followed distantly by diazepam, and lorazepam. The pharmacology of these drugs is discussed in Chapter 9.

c. Why will this patient require an analgesic prior to surgery, during the surgery, and during the immediate postoperative period?

With the exception of ketamine, neither parenteral nor currently available inhalational anesthetics are effective analgesics. Thus, analgesics typically are administered with general anesthetics to reduce anesthetic requirement and minimize hemodynamic changes produced by painful stimuli. Opioids are the primary analgesics used during the perioperative period because of the rapid and profound analgesia they produce. During the perioperative period, opioids often are given at induction to preempt responses to predictable painful stimuli (eg, endotracheal intubation and surgical incision). Subsequent doses either by bolus or by infusion are titrated to the surgical stimulus and the patient’s hemodynamic response.

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